Abstract
The human bacterial pathogen Neisseria meningitidis (Nm) is one of the world’s leading causative agents of systemic meningitis, which is characterised by inflammation of the meninges and more rarely, septicaemia. The high mortality rate and debilitating long term effects found in infants and young adults is due to the mounting of a large scale immune response by the host leading to severe inflammation and tissue death. The reasons as to how the meningococcus is able to breach innate immune barriers to cause this kind of infection, however, is still unclear. One important innate immune defence mechanism is the production of acute phase proteins such as C-Reactive Protein (CRP), which is known to opsonise pathogens such as N. meningitidis and enhance its uptake into human phagocytic cells. This investigation has demonstrated the enhanced uptake of CRP opsonised Nm into human macrophages and dendritic cells (DCs); two important innate immune cells which are some of the first to encounter the bacterium upon its dissemination through mucosal epithelium into the blood stream. Not only are these cells important phagocytes needed for the clearance of this pathogen, but dendritic cells in particular are the crucial link to the adaptive immune system, and play an important role in mounting effective, long term immunity to pathogens such as Nm. The enhanced uptake of CRP opsonised Nm was shown to occur by Fc gamma (γ) receptors I and II, which are expressed by both macrophages and dendritic cells. This was demonstrated by the blocking of Fcγ receptors with human IgG and specific antibodies to either receptor, which significantly reduced CRP enhanced uptake. The effect of CRP enhanced uptake of Nm into DC downstream immune responses was investigated to assess if CRP exacerbates or abrogates the hosts inflammatory response to Nm. Both unopsonised and CRP opsonised Nm were able to activate DCs and stimulate the up regulation of co-stimulatory and antigen presentation molecules, which is of significant importance in order to present processed Nm antigens to T cells and mount effective adaptive immune responses. Additionally, unopsonised Nm and CRP opsonised Nm were equally capable of up regulating the secretion of inflammatory cytokines from DCs. This suggests that CRP enhanced uptake of Nm by these phagocytic cells may be beneficial towards the host as despite the increased uptake of Nm by both cell types (potentially for phagocytic clearance), the pro-inflammatory cytokine response by DCs is not further exacerbated, thereby limiting inflammatory damage, which is known to the be the major contributor to the pathogenesis of meningococcal meningitis.